The dopamine D3 receptor (D3R) is involved in the craving response in drug addictions. Molecules which block D3R (D3R antagonists) are very valuable as potential therapeutics to treat substance abuse disorders. Poor pharmacokinetic properties and sub-optimal selectivity especially versus the closely related D2 receptor (D2R), have limited the clinical availability and utility of D3 antagonists. We have employed a progressive combination of in silico docking, synthesis and bioassays towards the discovery of novel, selective and potent D3R antagonists. The ligand design was based on a classical D3R pharmacophore comprising an amine-containing “head” moiety, a hydrocarbon linker “body” and an arylamide “tail” region. A tetrahydroisoquinoline motif representing the “head” portion was retained in all the analogues, with variations in an aryl linker moiety and the arylamide “tail” region. After docking at the D3R crystal structure, the top ranked analogues (based on Glide scores) were synthesized. Thereafter, the synthesized molecules were subjected to binding assays at dopamine receptors (D1R-D5R) <i>in vitro</i>. A number of selective D3R antagonists with moderate affinity were identified and this has provided important clues for future optimization. Results on our in silico studies as well as the synthesis and biological evaluation of the analogues will be presented.

Design, synthesis and biological evaluation of D3 antagonists with an aryl linker motif

256th National Meeting (2018)

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